The present invention relates to the treatment of mastalgia, or breast pain, with 4-hydroxy tamoxifen (4-OHT).
Mastalgia, also called “mastodynia,” constitutes the most common breast problem for which women consult general medical practitioners. Its severity varies, but mastalgia can be so prolonged and intense as to interfere with normal daily activities, and even to disable afflicted individuals. Mastalgia can be classified according to three general sources of pain: (1) cyclical mammary pain, (2) non-cyclical mammary pain, and (3) extramammary pain. Cyclical mastalgia results from physiological breast enlargement, caused by estrogen-dependent vascular changes, during the luteal phase of the menstrual cycle (Sambrook, 1987; Graham, 1995), and affects a majority of premenopausal women. Cyclical mastalgia also can recur in postmenopausal women on estrogen replacement therapy, with a dose-dependent effect (Callantine, 1975). One recent large survey showed that 67% of women aged 18-54 experience cyclical breast discomfort during the past 6 months, with 17% of them reporting pain lasting 7 or more days monthly (Ader, 1997). “Non-cyclical mastalgia,” as its name suggests, refers to pain in the breast that is not related to the menstrual cycle. A number of conditions give rise to non-cyclical mastalgia, including sclerosing adenosis, Tietz's syndrome and, rarely, breast cancer. Finally, extramammary mastalgia includes breast pain that is projected to the breast from other sources, as occurs, for example, when a patient feels pain from muscles or ribs that underlie the breasts.
Medical practitioners have experimented with many potential drug treatments for mastalgia. Non-cyclical mastalgia generally has failed to respond to drug therapy, causing some women to undergo bilateral mastectomy in extreme cases. For cyclical mastalgia, practitioners have administered diverse agents, including estrogen, androgens, pyridoxin (vitamin B6), α-tocopherol (vitamin E), bromocriptine and danazol (Fentiman, 1986). In particular, bromocriptine and danazol have shown some efficacy at relieving cyclical mastalgia, but also caused significant unwanted side effects, including nausea, vomiting, dizziness, headache, acne, sweating, amenorrhea and weight gain (Mansel et al., 1978; Gorins et al., 1984).
The cancer drug tamoxifen also has shown some promise for treating mastalgia. In several reported studies, orally administered tamoxifen reduced pain in 71-90% of patients with moderate to severe mastalgia. See Fentiman, 1986; Fentiman et al., 1988; Fentiman et al., 1989 (collectively, “Fentiman”). In subpopulations of patients with cyclical and non-cyclical mastalgia, tamoxifen reportedly was 94% and 56% effective, respectively, at reducing pain (Fentiman et al., 1988).
Tamoxifen has significant drawbacks in this context. Its action potentially impacts on every estrogen receptor in the body, and, as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. These effects increase the risk of endometrial cancer, endometrial hyperplasia and polyps, deep vein thrombosis and pulmonary embolism, changes in liver enzyme levels, and ocular disturbances, including cataracts. Additionally, mastalgia patients treated with oral tamoxifen reported having hot flashes, vaginal discharge, depression, amenorrhea, and nausea. See Ibis, 2002; Fentiman, supra.
Thus, a treatment for mastalgia that effectively reduced pain while provoking few systemic side effects would offer significant benefit.